Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

The large numbers of chromosomal rearrangements and somatic copy number alterations (SCNA) in osteosarcoma have hindered identification of common dependencies. Added to this is the paucity of adequate models that recapitulate the disease. To overcome the genomic heterogeneity between osteosarcoma tumors, Sayles and colleagues analyzed whole genome sequencing and gene expression in osteosarcoma tumors to identify patient-specific SCNAs in various genes including MYC, CDK4, and AURKB. The authors reasoned that copy number alterations were likely to select for amplicons that would be highly permissive for tumorigenesis and would thus provide therapeutically actionable targets. They developed patient-derived xenograft models of different osteosarcoma tumors and observed significant responses in animals that were treated with agents that “matched” the SCNA in each tumor.Expert Commentary: Survival for osteosarcoma patients is unchanged over 30 years. This paper utilizes the inherent genome instability of osteosarcoma tumors to identify patient-specific therapeutic vulnerabilities. Importantly, there was a strong correlation between an SCNA in a patient-derived xenograft model and drug response. These results support a personalized genome-directed therapy for osteosarcoma.Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY, et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov 2019;9:46–63.The development of organoids has opened up new opportunities to explore cancer biology directly in a testable system. Neal and colleagues used organoids from murine tumors and cancer patients to investigate immunotherapy in a dish. They cultured organoids with an air-liquid interface system that preserved myofibroblasts, macrophages, natural killer, T, and B cells. Focusing on the adaptive immune response, they examined the phenotype and repertoire of T- and B-cell antigen receptors. Single-cell RNA-based analysis confirmed that their long-term organoid cultures maintained the original T-cell clones found in the primary tumors and that the most abundant clones exhibited hallmarks of T-cell exhaustion. In addition, treatment with anti-PD1 or anti-PDL1 antibodies induced T-cell expansion and tumor cell killing in some cancer organoids, and PD1 expression on the T cells was the best biomarker of responsiveness.Expert Commentary: The use of 3D tumor organoids from cancer patients preserves the immune microenvironment and is a platform for testing new immunotherapeutics or prescreening patients for responsiveness to therapies.Neal JT, Li X, Zhu J, Giangarra V, Grzeskowiak CL, Ju J, et al. Organoid modeling of the tumor immune microenvironment. Cell 2018;175:1972–88.Mutation of SMARCB1 in highly aggressive, pediatric, malignant rhabdoid tumors (MRT) provided the first evidence for a role of the SWI/SNF chromatin-remodeling complex in cancer. Lack of genetic models for MRT has hampered both mechanistic dissection and the ability to test novel therapeutic regimens. Carugo and colleagues used a transuterine adenoviral injection system to create mosaic loss of SMARCB1 in mouse embryos, which allowed them to overcome the embryonic lethality of biallelic SMARCB1 inactivation. This mouse model produced focal tumors that recapitulated the histopathology and clinical features of MRT. A series of transcriptomic and bioinformatic analyses of these tumors revealed substantial ER stress, which they showed occurred via a Myc-p19ARF-p53-dependent pathway. This proteotoxicity resulted in increased autophagy and the unfolded protein response as an adaptive response within MRTs, sensitizing them to autophagocytic and proteasomal inhibitors.Expert Commentary: Development of a mouse model highlighted sensitivity of MRTs to proteotoxic stress, uncovering a novel therapeutic approach.Carugo A, Minelli R, Sapio L, Soeung M, Carbone F, Robinson FS, et al. p53 is a master regulator of proteostasis in SMARCB1-deficient malignant rhabdoid tumors. Cancer Cell 2019;35:204-20.e9. doi: 10.1016/j.ccell.2019.01.006.Circulating tumor cells (CTC) must survive in the circulation to enable seeding at distant metastatic sites. Szczerba and colleagues showed that the presence of CTC-white blood cell clusters was associated with worse progression-free survival compared to patients with increased numbers of single CTCs and that neutrophils were the predominant white blood cell in the clusters. In mouse models, CTC-neutrophil clusters were the most efficient metastasis-driving subpopulation of CTCs. Analysis of neutrophil-associated CTCs identified upregulation of genes linked to the cell cycle and concomitant increased proliferation. The adhesion molecule VCAM1 mediated the interaction between CTCs and neutrophils and depletion of neutrophils reduced CTC-neutrophil clusters and delayed metastasis development.Expert Commentary: Although rare, CTC-white blood cell clusters provide a possible target for reducing the metastatic fitness of CTCs.Szczerba BM, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J, et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 2019;566:553–7.Ferroptosis is an iron-dependent, nonapoptotic form of cell death, a regulatory pathway that suppresses tumor development. Ferroptosis is elicited by lipid peroxidation and is tightly regulated by SLC7A11, a central component of the cystine-glutamate antiporter. Utilizing biochemical purification approaches, Liu and colleagues identified OTUB1 as a bona fide regulator of SLC7A11. OTUB1 was overexpressed in human cancers and the OTUB1-SLC7A11 interaction was critical for tumor growth. Additionally, OTUB1 inactivation promoted ferroptosis in human cancer cells, primarily by downregulating SLC7A11. Moreover, the OTUB1-SLC7A11 interaction was tightly regulated by CD44 in human cancer cells.Expert Commentary: OTUB1 plays an essential role in controlling SLC7A11 stability and is also critically involved in CD44-mediated effects on ferroptosis in human cancer cells. This study elucidates the mechanism of ferroptosis regulation through SLC7A11 stability control in human cancers and suggests OTUB1 as a target in cancer therapy.Liu T, Jiang L, Tavana O, Gu W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Research; Published first February 1, 2019; doi: 10.1158/0008-5472.CAN-18-3037.Although mutant NRAS is the oncogenic driver in 20–30% of melanomas, targeting RAS proteins has been elusive. Yin and colleagues found a key role for the serine/threonine kinase STK19 in regulating mutant NRAS activity and tumorigenesis. STK19, which is mutated in 25% of melanomas, was found to phosphorylate NRAS at a conserved serine (S89), increasing NRAS activity and association with its downstream mediators. STK19 was required for NRAS-driven melanomagenesis in vitro and in vivo, and the gain-of-function STK19 D89N tumor mutation enhanced NRAS-driven melanogenesis. A novel ATP-competitive STK19 inhibitor was identified and shown to have significant efficacy against NRAS mutant melanoma in vitro and in vivo.Expert Commentary: This study has identified a novel target, STK19, for NRAS mutant melanoma. Further development of STK19 inhibitors may have a significant clinical impact for NRAS and potentially other RAS family member-driven malignancies.Yin C, Zhu B, Zhang T, Liu T, Chen S, Liu Y, et al. Pharmacological targeting of STK19 inhibits oncogenic NRAS-driven melanomagenesis. Cell 2019;176:1113–27.e16. doi: 10.1016/j.cell.2019.01.002.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.